New Insight into How Diabetes Leads to Blindness
Diabetic retinopathy is the leading cause of vision impairment and blindness among working age Americans. Retinopathy is caused by high blood glucose levels that lead to the abnormal development of tiny blood vessels in the eye. A number of landmark studies have demonstrated that intensive glycemic control reduces the development and progression of diabetic retinopathy. However, exactly how high blood glucose levels disrupt blood vessel development in the eye is not completely understood.
Michael D. Dennis, PhD, an American Diabetes Association Pathway to Stop Diabetes awardee, is exploring the idea that high blood glucose changes which genes get made into proteins in a manner that contributes to retinopathy.
His laboratory identified a molecular switch that determines which proteins are made in the part of the eye known as the retina. They found that the high blood glucose levels that occur with diabetes seem to flip the switch and cause a particular subset of genes to be made into proteins. Among these proteins that are increased when the switch is flipped is one called "vascular endothelial growth factor" (VEGF). VEGF causes blood vessels in the eye to multiply abnormally, and these increased blood vessels lead to the development of retinopathy.
Dr. Dennis has now identified one of the key factors involved in flipping the switch. It is a protein called "4E-BP1" and it is present at higher levels in the eyes of laboratory animals with diabetes. Dr. Dennis was able to make laboratory mice that do not have the 4E-BP1 protein and compare the impact of diabetes on vision when 4E-BP1 is present to when it is absent. Interestingly, he found that the diabetic animals lacking 4E-BP1 did not suffer from vison loss; unlike normal mice with 4E-BP1.
The researchers also tested the use of a drug that lowers blood glucose levels in diabetic animals. They discovered that reducing blood glucose levels with the drug also reduced the amount of 4E-BP1 in the retina, demonstrating a link between blood glucose levels and the amount of 4E-BP1 present in the retina.
Dr. Dennis and his colleagues then set out to study how 4E-BP1 itself is regulated by high blood glucose levels. These studies demonstrate that high blood glucose prevents 4E-BP1 from being broken down normally, which may be a key step leading to the switch that favors the production of proteins that ultimately lead to the development of diabetic retinopathy.
This discovery identifies a new set of molecules to investigate in order to develop new therapies for retinopathy, a debilitating complication of diabetes.
See Dr. Dennis's recent publication detailing this study:
Miller WP, Mihailescu ML, Yang C, Barber AJ, Kimball SR, Jefferson LS, Dennis MD. The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction. Invest Ophthalmol Vis Sci. 2016 Mar 1;57(3):1327-37.